Cytokine production is counter-regulated by evolutionarily ancient mechanisms. The cholinergic anti-inflammatory pathway is an anti-inflammatory neural mechanism for suppressing cytokine release by the immune system. It functions by signals carried via the vagus nerve that suppress cytokine release through a molecular mechanism that requires the alpha7 nicotinic acetylcholine receptor subunit (alpha7 nAChR). Direct electrical (or mechanical) stimulation of the vagus nerve attenuates cytokine release and prevents tissue injury in experimental animals with cytokine mediated diseases, including endotoxemia, hemorrhagic shock, ischemia-reperfusion, sepsis, colitis, and arthritis. The functional integrity of this pathway is critical for modulating the innate immune response to endotoxins, because eliminating the function, by either cutting the vagus nerve, or removing the alpha7 nAChR gene, renders animals exquisitely sensitive to otherwise innocuous quantities of endotoxins.
Early observations into the anatomic and functional basis of the cholinergic anti-inflammatory pathway implicate neural input to spleen as essential for vagus nerve mediated decreases of TNF during endotoxemia. Electrical stimulation of the vagus nerve in the neck attenuates TNF mRNA and protein levels in spleen, a major source of TNF in endotoxemia. Surgical ablation of the vagus nerve branches to the celiac ganglion disrupts the TNF-suppressive activity of cervical vagus nerve stimulation. Innervation to the spleen is provided by the splenic nerve, a catecholaminergic nerve that originates in the celiac ganglion. Since the cholinergic antiiflammatory pathway requires alpha7 nAChR signals, we examined how signals originating in vagus nerve reach the TNF-producing cells in spleen. Here we show that the splenic nerve is required for vagus nerve stimulation control of TNF production. Splenic nerve endings culminate adjacent to TNF producing macrophages and adjacent to T cells. Surprisingly, T cells are required for the functional integrity of the neural signals that inhibit TNF in spleen. As a result, we suggest methods and devices for treatment of disorders by stimulation of the inflammatory reflex (including the vagus nerve) in combination with modulation of T-Cells. Modulation of T-Cells, which may (in part) mediate the inflammatory reflex may help in further controlling the inflammatory reflex.
This application is related to U.S. Pat. No. 6,610,713; U.S. patent application Ser. No. 10/990,938, titled “Inhibition of Inflammatory Cytokine Production by Cholinergic Agonists and Vagus Nerve Stimulation,” filed Nov. 17, 2004; and U.S. patent application Ser. No. 11/318,075, titled “Treating Inflammatory Disorders by Electrical Vagus Nerve Stimulation,” filed Dec. 23, 2005. Each of these patents and pending applications is herein incorporated by reference in its entirety.